Chronic rheumatoid arthritis is an intractable autoimmune disease which is associated with swelling, inflammation, rigidity and pain of the joint and exhibits a clinical picture of generalized polyarthritis. That is, it is a generalized disease in which the living body recognizes self as nonself based on recognition defect of self and nonself, and attacks the self-tissue to cause abnormal immune response, resulting in inflammation of the connective tissue.
A major protein constituting the connective tissue is collagen and at least five kinds (I, II, III, IV and V types) collagens are found in homoiotherm. The joint contains joint cartilage which contains type II collagen as a main component. Major diseased site of chronic rheumatoid arthritis is synovial tissue where infiltration of lymphocyte consisting mainly of T-cells is recognized. Also it has conventionally been known that clone, which specifically reacts with type II collagen, exists in CD4+T cells which infiltrated into synovial membrane. As an antigen capable of producing self-reactive T-cells, proteoglycan, adenovirus, EB virus and heat shock protein are known, in addition to type II collagen. Among them, type II collagen is considered to be one of most prominent self-antigens because it is a main component of the cartilage and exists in the joint. Chronic rheumatoid arthritis provokes the breakage of cartilage and bone while repeating remission and aggravation to cause structural deformation of the peripheral joint.
As a drug therapy for chronic rheumatoid arthritis, an anti-inflammatory steroid (for example, prednisolone), nonsteroidal anti-inflammatory drugs (for example, indomethacin, aspirin), an immunosuppressive agent (for example, cyclosporin A, tacrolimus (FK506), methotrexate, cyclophosphamide, azathioprine) and a disease-modifying antirheumatic drug (for example, gold salt preparation) are used. Although the anti-inflammatory agent can alleviate pain and swelling by controlling inflammation, it is hard to suppress the progression of this disease. It is considered that, among the above immunosuppressive agents, cyclosporin A and tacrolimus exert an immunosuppression effect by suppressing the production of IL-2 from T-cells. Although a mechanism of the action of the disease-modifying antirheumatic drug has never been elucidated, it has an effect for sedation and remission of this disease.
As described above, any drugs merely relieve the symptom and delay the progression of the disease and also revoke side effects involved in administration for a long period, and thus these drugs are not satisfactory drugs. Therefore, it is strongly required to develop a novel remedy for chronic rheumatoid arthritis.
It is known that the aminostilbazole derivative of the present invention has an intense anticancer activity and very low toxicity (International Publication WO95/27699).